Sustained drug delivery implant

ABSTRACT

Biocompatible intraocular implants may include a brimonidine free base and a biodegradable polymer associated with the brimonidine free base to facilitate the release of the brimonidine free base into an eye with the polymer matrix lasts a period of time of not more than twice the drug release duration, but more than the drug release duration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/354,692, filed Mar. 15, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/350,577 filed Nov. 14, 2016, now U.S. Pat. No.10,231,926, issued Mar. 19, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/218,324 filed Mar. 18, 2014, now issued as U.S.Pat. No. 9,610,246, which is a continuation of U.S. patent applicationSer. No. 14/181,250 filed Feb. 14, 2014, now abandoned, which claims thebenefit of U.S. Provisional Application No. 61/765,554 filed Feb. 15,2013, the entire content of each application is incorporated herein byreference.

BACKGROUND Field

The disclosure of the present application generally relates to drugdelivery implants, and more specifically, drug delivery implants used totreat ocular conditions.

Description of the Related Art

Diabetic retinopathy is the leading cause of blindness among adults aged20 to 74 years. It is estimated that 75,000 new cases of macular edema,65,000 cases of proliferative retinopathy, and 12,000 to 24,000 newcases of blindness arise each year. Retinitis pigmentosa (RP) is aheterogeneous group of inherited neurodegenerative retinal diseases thatcause the death of photoreceptor cells (rods and cones) that eventuallyleads to blindness. Glaucoma is a multifactorial optic neuropathyresulting from loss of retinal ganglion cells, corresponding atrophy ofthe optic nerve, and loss of visual function, which is manifestedpredominantly by visual field loss and decreased visual acuity and colorvision. Geographic atrophy (“GA”) is one of 2 forms of the advancedstage of Age-Related Macular Degeneration (“AMD”). The advanced stage ofAMD refers to that stage in which visual acuity loss can occur from AMD.Retinal detachments are a significant cause of ocular morbidity. Thereare 3 types of retinal detachment: rhegmatogenous, tractional, andexudative.

Brimonidine (5-bromo-6-(2-imidazolidinylideneamino) quinoxaline) is analpha-2-selective adrenergic receptor agonist effective for treatingopen-angle glaucoma by decreasing aqueous humor production andincreasing uveoscleral outflow. Brimonidine tartrate ophthalmic solution0.2% (marketed as ALPHAGAN®) was approved by the US Food and DrugAdministration (FDA) in September 1996 and in Europe in March 1997(United Kingdom). Brimonidine tartrate ophthalmic solution with Purite®0.15% and 0.1% (marketed as ALPHAGAN® P) was approved by the FDA inMarch 2001 and August 2005, respectively. These formulations arecurrently indicated for lowering IOP in patients with open-angleglaucoma (OAG) and ocular hypertension (OHT).

A neuroprotective effect of brimonidine tartrate has been shown inanimal models of optic nerve crush, moderate ocular hypertension,pressure-induced ischemia, and vascular ischemia. The neuroprotectiveeffect of topical applications of brimonidine tartrate has also beenexplored clinically in patients with glaucoma, age-related maculardegeneration, retinitis pigmentosa, diabetic retinopathy, and acutenon-arteritic anterior ischemic optic neuropathy. However, certainlimitations exist with the use of brimonidine tartrate in intraocularimplants. For example, because of the size of the brimonidine tartratemolecule, the amount of drug that can be loaded into an implant may belimited. Also, the hydrophilic nature of brimonidine tartrate may limitthe ability of the drug's use in sustained release formulations.

SUMMARY

Accordingly, an embodiment provides an intraocular implant for thetreatment of a posterior ocular condition in a human patient including abiodegradable polymer matrix including at least one biodegradablepolymer and a brimonidine free base agent, wherein the implant can beconfigured to deliver the brimonidine free base agent to the vitreous ofan eye of a patient suffering from a posterior ocular condition for abrimonidine free base agent delivery duration of up to six months andwherein the biodegradable polymer matrix is configured to completely oralmost completely degrade, once placed into the vitreous of the eye,within a period of time of about two times the brimonidine free baseagent delivery duration or less. In some embodiments, the brimonidinefree base agent is present in the implant in an amount of about 50% byweight of the implant, based on the total weight of the implant. In someembodiments, the implant can have a rod shape, and the rod shape canhave a rod diameter of about 350 μm and a rod length of about 6 mm.According to other embodiments, the brimonidine free base agent isdispersed within the biodegradable polymer matrix. In some embodiments,the at least one biodegradable polymer includespoly(D,L-lactide-co-glycolide) and poly(D,L-lactide). In someembodiments, the biodegradable polymer matrix includes at least onepolymer selected from the group consisting of acid-end cappedpoly(D,L-lactide-co-glycolide) and acid-end capped poly(D,L-lactide). Insome embodiments, the brimonidine free base agent delivery duration isin the range of about 1 month to about 6 months.

These and other embodiments are described in greater detail below.

BRIEF DESCRIPTION OF THE FIGURES

These and other features will now be described with reference to thedrawings summarized below. These drawings and the associated descriptionare provided to illustrate one or more embodiments and not to limit thescope of the invention.

FIG. 1 illustrates brimonidine tartrate implant formulation drug releaseprofiles in 0.01 M PBS with a pH of 7.4 at 37° C., according tocomparative example formulations.

FIG. 2 shows brimonidine free base implant formulation drug releaseprofiles in 0.01 M PBS with a pH of 7.4 at 37° C., according to exampleformulations.

FIG. 3 shows brimonidine tartrate implant formulation drug releaseprofiles in Albino rabbits, according to comparative exampleformulations.

FIG. 4 shows brimonidine tartrate implant formulation drug releaseprofiles in Cyno monkeys, according to comparative example formulations.

FIG. 5 illustrates brimonidine free base implant formulation drugrelease profiles in Albino rabbits, according to example formulations.

FIG. 6 illustrates brimonidine free base implant formulation drugrelease profiles in Cyno monkeys, according to example formulations.

FIG. 7 shows the drug concentration of brimonidine tartrate implantformulations in the retina (optic nerve) of Albino rabbits over timeaccording to comparative example formulations. The dotted line indicatesthe human α2A EC90 concentration.

FIG. 8 shows the drug concentration of brimonidine free base implantformulations in the retina (optic nerve) of Albino rabbits over timeaccording to example formulations. The dotted line indicates the humanα2A EC90 concentration.

FIG. 9 illustrates the drug concentration of brimonidine free baseimplant formulations in the retina (macula) of Cyno monkeys over timeaccording to example formulations. The dotted line indicates the humanα2A EC90 concentration. For comparison, the CE1 brimonidine formulationis included.

FIG. 10 illustrates the polymer matrix degradation of brimonidinetartrate implant formulations in Cyno monkeys over time, according tocomparative example formulations.

FIG. 11 shows the polymer matrix degradation of brimonidine free baseimplant formulations in Cyno monkeys over time, according to exampleformulations.

FIG. 12 shows the implant image when incubating in PBS (pH 7.4, 0.01N)at 37° C.

DETAILED DESCRIPTION

In general terms, an embodiment relates to brimonidine free basesustained delivery for back-of-the-eye therapeutic applications. In someembodiments, the brimonidine free base is formulated into an implantwith one or more polymers in a polymer matrix, the polymers selected inorder to give a target sustained delivery of the brimonidine free baseand/or a target degradation of the one or more polymers. According tosome embodiments, formulations of brimonidine free base andbiodegradable polymer or polymers are created such that the polymermatrix will be degraded within a period of not more than twice thebrimonidine free base release duration, but more than the brimonidinefree base release duration. According to some embodiments, thebrimonidine free base drug delivery system exhibits a target drugdelivery duration of one to six months and a target matrix degradationtime of two to twelve months.

Embodiments herein disclose new drug delivery systems, and methods ofmaking and using such systems, for extended or sustained drug releaseinto an eye, for example, to achieve one or more desired therapeuticeffects. The drug delivery systems can be in the form of implants orimplant elements that can be placed in an eye. The systems and methodsdisclosed in some embodiments herein can provide for extended releasetime of one or more therapeutic agent or agents. Thus, for example, apatient who has received such an implant in their eye can receive atherapeutic amount of an agent for a long or extended time periodwithout requiring additional administrations of the agent. According tosome embodiments an implant may also only remain within the eye of apatient for a targeted or limited amount of time before it degradescompletely or nearly completely. By limiting the amount of time aforeign object, such as an implant is in a patient's eye or vitreous, apatient's comfort is optimized and their risk for infection or othercomplications is minimized. Also, complications that may arise from animplant colliding with the cornea or other part of the eye in thedynamic fluid of the vitreous can be avoided.

As used herein, an “intraocular implant” refers to a device or elementsthat is structured, sized, or otherwise configured to be placed in aneye. Intraocular implants are generally biocompatible with physiologicalconditions of an eye. Intraocular implants may be placed in an eyewithout disrupting vision of the eye.

As used herein, “therapeutic component” refers to a portion of anintraocular implant comprising one or more therapeutic agents orsubstances used to treat a medical condition of the eye. The therapeuticcomponent may be a discrete region of an intraocular implant, or it maybe homogenously distributed throughout the implant. The therapeuticagents of the therapeutic component are typically ophthalmicallyacceptable, and are provided in a form that does not cause adversereactions when the implant is placed in the eye.

As used herein, an “ocular condition” is a disease ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. The eye can include the eyeball and the tissues and fluids thatconstitute the eyeball, the periocular muscles (such as the oblique andrectus muscles) and the portion of the optic nerve which is within oradjacent the eyeball.

An “anterior ocular condition” is a disease, ailment, or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular condition canaffect or involve the conjunctiva, the cornea, the anterior chamber, theiris, the posterior chamber (located behind the retina, but in front ofthe posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

A “posterior ocular condition” is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve or optic disc, and blood vessels and nerves that vascularizeor innervate a posterior ocular region or site.

Thus a posterior ocular condition can include a disease, ailment orcondition such as, but not limited to, acute macular neuroretinopathy;Behcet's disease; geographic atrophy; choroidal neovascularization;diabetic uveitis; histoplasmosis; infections, such as fungal, bacterial,or viral-caused infections; macular degeneration, such as acute maculardegeneration, non-exudative age related macular degeneration andexudative age related macular degeneration; edema, such as macularedema, cystoids macular edema and diabetic macular edema; multifocalchoroiditis; ocular trauma which affects a posterior ocular site orlocation; ocular tumors; retinal disorders, such as central retinal veinocclusion, diabetic retinopathy (including proliferative diabeticretinopathy), proliferative vitreoretinopathy (PVR), retinal arterialocclusive disease, retinal detachment, uveitic retinal disease;sympathetic ophthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uvealdiffusion; a posterior ocular condition caused by or influenced by anocular laser treatment; or posterior ocular conditions caused by orinfluenced by a photodynamic therapy, photocoagulation, radiationretinotherapy, epiretinal membrane disorders, branch retinal veinocclusion, anterior ischemic optic neuropathy, non-retinopathy diabeticretinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can beconsidered a posterior ocular condition because the therapeutic goal isto prevent the loss of or reduce the occurrence of loss of vision due todamage to or loss of retinal cells or optic nerve cells (e.g.neuroprotection).

The terms “biodegradable polymer” or “bioerodible polymer” refer to apolymer or polymers which degrade in vivo, and wherein erosion of thepolymer or polymers over time occurs concurrent with and/or subsequentto the release of a therapeutic agent. A biodegradable polymer may be ahomopolymer, a copolymer, or a polymer comprising more than twopolymeric units. In some embodiments, a “biodegradable polymer” mayinclude a mixture of two or more homopolymers or copolymers.

The terms “treat”, “treating”, or “treatment” as used herein, refer toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of therapeutic agent needed to treat an ocularcondition, or reduce or prevent ocular injury or damage.

Those skilled in the art will appreciate the meaning of various terms ofdegree used herein. For example, as used herein in the context ofreferring to an amount (e.g., “about 6%”), the term “about” representsan amount close to and including the stated amount that still performs adesired function or achieves a desired result, e.g. “about 6%” caninclude 6% and amounts close to 6% that still perform a desired functionor achieve a desired result. For example, the term “about” can refer toan amount that is within less than 10% of, within less than 5% of,within less than 0.1% of, or within less than 0.01% of the statedamount.

Intraocular implants can include a therapeutic component and a drugrelease control component or components. The therapeutic agent cancomprise, or consist essentially of an alpha-2 adrenergic receptoragonist. The alpha-2 adrenergic receptor agonist may be an agonist oragent that selectively activates alpha-2 adrenergic receptors, forexample by binding to an alpha-2 adrenergic receptor, relative to othertypes of adrenergic receptors, such as alpha-1 adrenergic receptors. Theselective activation can be achieved under different conditions, such asconditions associated with the eye of a human patient.

The alpha-2 adrenergic receptor agonist of the implant is typically anagent that selectively activates alpha-2 adrenergic receptors relativeto alpha-2 adrenergic receptors. In certain implants, the alpha-2adrenergic receptor agonist selectively activates a subtype of thealpha-2 adrenergic receptors. For example, the agonist may selectivelyactivate one or more of the alpha-2a, the alpha-2b, or the alpha-2creceptors, under certain conditions, such as physiological conditions.Under other conditions, the agonist of the implant may not be selectivefor alpha-2 adrenergic receptor subtypes. The agonist may activate thereceptors by binding to the receptors, or by any other mechanism.

According to some embodiments, the alpha-2 receptor antagonist used isbrimonidine. Brimonidine is a quinoxaline derivative having thestructure:

Brimonidine, an organic base, is publicly available as brimonidine freebase. Brimonidine free base is generally hydrophobic.

In some embodiments, the alpha-2 adrenergic receptor antagonist may be apharmaceutically acceptable acid addition salt of brimonidine. One suchsalt can be brimonidine tartrate (AGN 190342-F,5-bromo-6-(2-imidazolidinylideneamino) quinoxaline tartrate). Bothbrimonidine free base and brimonidine tartrate are chemically stable andhave melting points higher than 200° C.

Thus, an intraocular implant can comprise, consist of, or consistessentially of a therapeutic agent such as an alpha-2 adrenergicreceptor agonist such as a brimonidine salt alone (such as brimonidinetartrate), a brimonidine free base alone, or mixtures thereof.

The use of brimonidine free base in solid implant formulations hasseveral advantages over brimonidine tartrate, such as the lowersolubility of brimonidine free base lowers potential drug burst effect,and the free base drug equivalent dose per implant can be higher underthe same weight. Thus, according to some embodiments, no brimonidinetartrate is included in an intraocular implant. According to someembodiment, the only therapeutic agent used in an intraocular implant isbrimonidine free base.

The alpha-2 adrenergic receptor agonist may be in a particulate orpowder form and entrapped by the biodegradable polymer matrix. Accordingto an embodiment, the alpha-2 adrenergic receptor agonist is abrimonidine free base having a D90 particle size of less than about 20μm. According to another embodiment, the alpha-2 adrenergic receptoragonist is a brimonidine free base having a D90 particle size of lessthan about 10 μm. According to another embodiment, the alpha-2adrenergic receptor agonist is a brimonidine free base having a D90particle size in the range of about 10 μm to about 20 μm.

According to some embodiments, implants can be formulated with particlesof the brimonidine free base agent dispersed within the bioerodiblepolymer matrix. According to some embodiments, the implants can bemonolithic, having the therapeutic agent homogenously distributedthrough the biodegradable polymer matrix, or encapsulated, where areservoir of active agent is encapsulated by the polymeric matrix. Insome embodiments, the therapeutic agent may be distributed in anon-homogeneous pattern in the biodegradable polymer matrix. Forexample, in an embodiment, an implant may include a first portion thathas a greater concentration of the therapeutic agent (such asbrimonidine free base) relative to a second portion of the implant.

The alpha-2 adrenergic receptor agonist can be present in an implant inan amount in the range of about 20% to about 70% by weight of theimplant, based on the total weight of the implant. In some embodiments,the alpha-2 adrenergic receptor agonist can be present in an implant inan amount in the range of about 40% to about 60% by weight of theimplant, based on the total weight of the implant. In an embodiment, thealpha-2 adrenergic receptor agonist can be present in an implant in anamount of about 40% by weight of the implant, based on the total weightof the implant. In another embodiment, the alpha-2 adrenergic receptoragonist can be present in an implant in an amount of about 50% by weightof the implant, based on the total weight of the implant. In an exampleembodiment, brimonidine free base can be present in an implant in anamount of about 50% by weight of the implant, about 55% by weight of theimplant, about 60% by weight of the implant, or about 70% by weight ofthe implant, based on the total weight of the implant.

Suitable polymeric materials or compositions for use in the implant caninclude those materials which are compatible with the eye so as to causeno substantial interference with the functioning or physiology of theeye. Such materials can be at least partially or fully biodegradable.

Examples of suitable polymeric materials for the polymer matrix includepolyesters. For example, polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof may be used for the polymer matrix. In some embodiments, apolyester, if used, may be a homopolymer, a copolymer, or a mixturethereof.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation can be controlled, in part, by theratio of glycolic acid to lactic acid. The mol percentage (% mol) ofpolylactic acid in the polylactic acid polyglycolic acid (PLGA)copolymer can be between 15 mol % and about 85 mol %. In someembodiments, the mol percentage of polylactic acid in the (PLGA)copolymer is between about 35 mol % and about 65 mol %. In someembodiments, a PLGA copolymer with 50 mol % polylactic acid and 50 mol %polyglycolic acid can be used in the polymer matrix.

The polymers making up the polymer matrix may also be selected based ontheir molecular weight. Different molecular weights of the same ordifferent polymeric compositions may be included in the implant tomodulate the release profile. In some embodiments, the release profileof the therapeutic agent and the degradation of the polymer may beaffected by the molecular weight of one or more polymers in the polymermatrix. In some embodiments, the molecular weight of one or more poly(D,L-lactide) components may be advantageously selected to control therelease of the therapeutic agent and the degradation of the polymer.According to some embodiments, the average molecular weight of apolymer, such as poly (D,L-lactide), may be “low.” According to someembodiments, the average molecular weight of a polymer, such as poly(D,L-lactide), may be “medium.” According to some embodiments, only lowmolecular weight poly(D,L-lactide) is included in a polymer matrix in anintraocular implant. According to some embodiments, high molecularweight (Mw) poly(D,L-lactide)s are not present in the biodegradablepolymer matrix or they are only present in a negligible amount (about0.1% by weight of an implant, based on the total weight of the implant).By limiting the amount of high molecular weight poly(D,L-lactide)present in an implant, the matrix degradation duration may be shortened.

Some example polymers that may be used alone or in combination to formthe polymer matrix include those listed in TABLE A below, the datasheets of the commercially available polymers are incorporated byreference, in their entirety:

TABLE A Trade Name of Molecular Commercially Weight Available Intrinsic(low, Polymer (From Viscosity medium, EVONIK) Polymer (dL/g) high)RG502S 50:50 poly (D, L- 0.16-0.24 low lactide-co-glycolide) RG502H50:50 poly (D, L- 0.16-0.24 low lactide-co-glycolide), acid end cappedRG504 50:50 poly (D, L- 0.45-0.60 medium lactide-co-glycolide) RG50550:50 poly (D, L- 0.61-0.74 medium lactide-co-glycolide) RG752S 75:25poly (D, L- 0.16-0.24 low lactide-co-glycolide) RG755 75:25 poly (D, L-0.50-0.70 medium lactide-co-glycolide) RG858S 85:15 poly (D, L- 1.3-1.7medium lactide-co-glycolide) R202H poly (D, L-lactide), 0.16-0.24 lowacid end capped R203S poly (D, L-lactide) 0.25-0.35 medium R208 poly (D,L-lactide) 1.8-2.2 high

The biodegradable polymer matrix of the intraocular implant can comprisea mixture of two or more biodegradable polymers. In some embodiments,only one biodegradable polymer listed above is used in the biodegradablepolymer matrix. In some embodiments, any one of the biodegradablepolymers listed in the above chart can be used in an amount in the rangeof 12.5% w/w to 70% w/w each in a drug delivery system or implant. Insome embodiments, any one of the biodegradable polymers listed in theabove chart can be used in an amount in the range of 25% w/w to 50% w/weach in a drug delivery system or implant. In some embodiments, any oneof the biodegradable polymers listed in the above chart can be used inan amount in the range of 20% w/w to 40% w/w each in a drug deliverysystem or implant. In some embodiments, any one of the biodegradablepolymers listed in the above chart can be used in an amount of about 15%w/w, about 25% w/w, about 12.5% w/w, about 37.5% w/w, about 40% w/w,about 50% w/w, or about 60% w/w each in a drug delivery system orimplant. For example, the implant may comprise a mixture of a firstbiodegradable polymer and a different second biodegradable polymer. Oneor more of the biodegradable polymers may have terminal acid groups.

In some embodiments, release of a therapeutic agent from a biodegradablepolymer matrix in an intraocular implant can be the consequence ofvarious mechanisms and considerations. Release of the agent can beachieved by erosion of the biodegradable polymer matrix followed byexposure of previously embedded drug particles to the vitreous of an eyereceiving the implant, and subsequent dissolution and release of thetherapeutic agent. The release kinetics by this form of drug release aredifferent than that through formulations which release agent by polymerswelling alone, such as with hydrogel or methylcellulose. The parameterswhich may determine the release kinetics include the size of the drugparticles, the water solubility of the drug, the ratio of drug topolymer, and the erosion rate of the polymers.

According to some embodiments, compositions and methods extend thebrimonidine free base delivery in the vitreous with concomitantlymoderate matrix degradation duration. The sustained ocular drug deliverycan be achieved by formulating brimonidine free base with properlyselected blend of bioerodible poly(D,L-lactide) and/orpoly(D,L-lactide-co-glycolide).

According to some example embodiments, a drug delivery system or implantcan contain a polymer matrix with an acid-capped poly (D,L-lactide) inan amount in the range of 25% w/w to about 50% w/w. According to someexample embodiments, a drug delivery system or implant can contain apolymer matrix with an acid-capped 50:50 poly (D,L-lactide-co-glycolide)in an amount in the range of about 25% w/w to about 50% w/w or about37.5% to about 50% w/w of the implant. According to some exampleembodiments, a drug delivery system or implant can contain a polymermatrix with an acid-capped 75:25 poly (D,L-lactide-co-glycolide) in anamount in the range of about 25% w/w to about 50% w/w or about 15% w/wto about 50% w/w of the implant. According to some example embodiments,a drug delivery system or implant can contain a polymer matrix with anacid-capped 85:15 poly (D,L-lactide-co-glycolide) in an amount in therange of about 25% w/w to about 50% w/w or about 30% to about 60% w/w ofthe implant.

The drug delivery systems are designed to release brimonidine free baseat therapeutic levels to the vitreous for a sustained period of time(the brimonidine free base delivery duration), then degrade over periodof time in the range of half the brimonidine free base delivery durationto a time equivalent to the brimonidine free base delivery duration.According to other embodiments, the drug delivery system including thepolymer matrix can degrade over a period of time of about one quarterthe brimonidine free base delivery duration to about one half thebrimonidine free base delivery duration. According to other embodiments,the drug delivery system including the polymer matrix can degrade over aperiod of time of about one third the brimonidine free base deliveryduration to about one half the brimonidine free base delivery duration.According to other embodiments, the drug delivery system including thepolymer matrix can degrade over a period of time equivalent to about thebrimonidine free base delivery duration to about twice the brimonidinefree base delivery duration. For example, in an embodiment, anintraocular implant may include a mixture of brimonidine free base and abiodegradable polymer matrix that releases brimonidine free base over aperiod of time of three months, then the polymer matrix degrades for aperiod of an additional 2 months until the implant is completelydegraded or almost completely degraded. According to some embodiments,the brimonidine free base delivery duration is a period of time in therange of about 1 month to about 6 months, about 1 month to about 5months, about 1 month to about 3 months, about 1 month to about 4months, about 2 months to about 4 months, or about 3 months to about 6months. According to some embodiments, the polymer matrix degradationtime for the total drug delivery system is in the range of about 1 monthto about 7 months, about 1 month to about 6 months, about 3 months toabout 7 months, about 1 month to about 4 months, about 3 months to about4 months, about 4 months to about 5 months, about 5 months to about 7months, or about 3 months to about 6 months. According to someembodiments, the polymer matrix degradation time for the drug deliverysystem is fewer than 10 weeks, fewer than 8 weeks, fewer than 6 weeks,or fewer than 4 weeks.

According to one example embodiment, a biodegradable intraocular implantcomprises brimonidine free base associated with a biodegradable polymermatrix, which comprises a mixture of different biodegradable polymers.The brimonidine free base is present in the implant in an amount of 50%by weight, based on the total weight of the implant. A firstbiodegradable polymer is an acid end capped poly (D,L-lactide) having aninherent viscosity of between 0.16 dL/g and 0.24 dL/g, and comprising25% by weight of the implant, based on the total weight of the implant.A second biodegradable polymer is a PLGA copolymer having 75 mol %polylactic acid and 25 mol % polyglycolic acid. The PLGA copolymer hasan inherent viscosity of between 0.16 dL/g and 0.24 dL/g, and the PLGAcopolymer comprises 25% of weight of the implant, based on the totalweight of the implant. Such a mixture is effective in releasing aneffective amount of the brimonidine free base over a delivery durationof about three months, then degrading the polymer matrix over the spanof one-two additional months, less than twice the brimonidine free basedelivery duration.

According to another example embodiment, a biodegradable intraocularimplant comprises brimonidine free base associated with a biodegradablepolymer matrix, which comprises a single type of biodegradable polymer.The brimonidine free base is present in the implant in an amount of 50%by weight, based on the total weight of the implant. In this embodiment,the biodegradable polymer matrix is made of a PLGA copolymer having 85mol % polylactic acid and 15 mol % polyglycolic acid. The PLGA copolymerhas an inherent viscosity of between 1.3 dL/g and 1.7 dL/g, and the PLGAcopolymer comprises 50% of weight of the implant, based on the totalweight of the implant. Such a mixture is effective in releasing aneffective amount of the brimonidine free base over a delivery durationof about three or four months, then degrading the polymer matrix overthe span of one-two additional months, less than twice the brimonidinefree base delivery duration.

Manufacture of Implants

According to some embodiments, intraocular implants can be formedthrough suitable polymer processing methods. In an embodiment, a mixtureof a therapeutic agent (such as brimonidine free base) may be blendedwith PLA and/or PLGA polymers in a mixer, such as a Turbula mixer. In anembodiment, the intraocular implants are formed by extrusion. Extrusioncan be performed by a suitable extruder, such as a Haake extruder. Afterthe therapeutic agent and the polymer matrix have been blended together,they can then be force fed into an extruder and extruded into filaments.The extruded filaments may then be cut into implants with a targetweight. In some embodiments, a 800 μg implant may be cut to deliverabout 300 μg, 400 μg, or 500 μg of drug over the brimonidine free basedelivery duration. Implants can then be loaded into an injection device,such as a 25 G applicator and sterilized. According to some embodiments,the extruded filaments are cut to a weight of less than 1000 μg, lessthan 800 μg, or less than 600 μg. In some embodiments, the implants canbe gamma sterilized. The implants can be gamma sterilized at doses suchas 20 kGy to 60 kGy, 25 kGy to 50 kGy, 25 kGy to 40 kGy, and the like.

Methods for Treatment

According to an embodiment, a method for treating a posterior ocularcondition includes administering an implant, such as the implantsdisclosed herein, to a posterior segment of an eye of a human or animalpatient, and preferably a living human or animal. In some embodiments, amethod of treating a patient may include placing the implant directlyinto the posterior chamber of the eye. In some embodiments, a method oftreating a patient may comprise administering an implant to the patientby at least one of intravitreal injection, subconjunctival injection,subtenon injections, retrobulbar injection, and suprachoroidalinjection.

In at least one embodiment, a method of treating retinitis pigmentosa,glaucoma, macular degeneration, and/or geographic atrophy in a patientcomprises administering one or more implants containing brimonidine freebase, as disclosed herein, to a patient by at least one of intravitrealinjection, subconjunctival injection, sub-tenon injection, retrobulbarinjection, and suprachoroidal injection. A syringe apparatus includingan appropriately sized needle, for example, a 27 gauge needle or a 30gauge needle, can be effectively used to inject the composition with theposterior segment of an eye of a human or animal. According to someembodiments, no more than one injection is administered to the patientto treat the condition. According to other embodiments, more than oneinjection is administered to the patient to treat the condition.

Examples

Example intraocular implants containing brimonidine tartrate orbrimonidine free base and a biodegradable polymer matrix were createdand tested for their release and degradation properties. The brimonidinetartrate or brimonidine free base was first weighed and blended with PLAand/or PLGA polymers in a Turbula mixer for 30 minutes. The resultingpowder blend was then fed to the Haake extruder by a force feeder. Theextruded filaments were cut to implants with a target weight, e.g., 857μg or 800 μg to deliver 300 μg brimonidine tartrate or 400 μgbrimonidine free base per implant. Implants were loaded into 25 Gapplicators and gamma-sterilized at 25 to 40 kGy dose. The potency perimplant was confirmed by a HPLC assay.

Examples and Comparative Examples of formulation compositions usingbrimonidine tartrate (as Comparative Examples 1-4) and brimonidine freebase (Examples 1-4) as the drug are shown in Tables B and C, and theirdrug release profiles are shown in FIGS. 1 and 2, respectively. In FIGS.1 and 2, they axis is number of days and they axis is the percentage (%)of total release. For in vitro drug release testing, four implants pereach formulation were randomly cut from extruded filaments, gammasterilized, and incubated in 10 mL of 0.01M PBS pH 7.4 in a shakingwater bath set at 37° C. and 50 rpm. The drug release was sampled atdesignated time point, and the drug content was analyzed by a HPLCassay. The release medium was completely replaced with fresh mediumduring each sampling time point. The polymer Mw degradation rateconstant k, as determined by incubating implant samples in 0.01M PBS pH7.4 at 25° C. and their Mw determined by size exclusion chromatography,is included in Tables B and C as well.

TABLE B Brimonidine tartrate formulation comparative examplecomposition, dimension and degradation kinetic parameters BrimonidinePolymer Excipient, % w/w Implant Implant Implant k at 37 C. Tartrate, RR R RG RG Diameter Length Weight (1/day), in Formulation % w/w 202H 203S208 752S 858S (μm) (mm) (μg) vitro CE 1 35 40 25 356 ~6 857 0.0041 CE235 65 356 ~6 857 0.0033 CE3 35 48 17 356 ~6 857 0.0073 CE4 35 15 40 10356 ~6 857 0.0064

TABLE C Brimonidine free base example formulation composition, dimensionand degradation kinetic parameter Brimonidine Polymer Excipient, % w/wImplant Implant Implant k at 37 C. free base, R RG RG RG RG DiameterLength Weight (1/day), in Formulation % w/w 202H 502H 502S 752S 858S(μm) (mm) (μg) vitro EX 1 50 50 356 ~6 800 0.02 EX 2 50 50 356 ~6 8000.012 EX 3 50 25 25 356 ~6 800 0.012 EX 4 50 37.5 12.5 356 ~6 800 0.057

The polymer matrix degradation was then analyzed both in vitro and invivo. For in vitro study, the polymer Mw degradation rate constant k asdescribed above was used to calculate the degradation time for thepolymer Mw degraded to 1000 Da t(1000) by assuming the degradationfollows first order kinetics. For in vivo study, the polymer matrixdegradation was determined by harvesting the implant samples that wereinjected to the vitreous of New Zealand rabbit. The results aresummarized in Table D.

TABLE D Brimonidine formulation in vitro and in vivo drug release andpolymer matrix degradation time In Vitro Rabbit Calc. Matrix Drug DrugDegradation Drug Matrix Substance Formulation Release t(1000) ReleaseDegradation Brimo CE 1 6 months ~30 months >6 months >>6 months TartrateCE 2 4 months ~28 months 5 months >>6 months CE 3 4 months ~15 months4.5 months >>6 months CE 4 3 months ~14 months 3 months >6 month BrimoEX 1 3 months ~3 months ~2 months 2 months Free EX 2 4 months ~7 months~3 months 4 months Base EX 3 3 months ~5 months ~3 months 3 months EX 41 month ~1 months ~1 month 1 month

In Vitro Testing of Intraocular Implants Containing Brimonidine and aBiodegradable Polymer Matrix Weight Loss Study

For the implant weight loss study, each implant was first weighed, movedto a plastic micromesh cassette, and incubated in a glass jar filledwith PBS (pH 7.4, 0.01M) before placed in a shaking water bath set at37° C. and 50 rpm. The implants were harvested at designated time pointsand dried under vacuum. The weights of the dried implants were recordedand the implant weight loss was calculated. The results are summarizedin Table E and show that the brimonidine free base implants lose weightmore quickly than those of brimonidine tartrate, implying andillustrating the difference in matrix degradation rate.

TABLE E Implant weight loss in PBS (pH 7.4, 0.01M) at 37° C. RemainingWeight Time (wk) CE 1 CE 2 CE 3 CE 4 EX 1 EX 2 EX 3 EX 4 1 99.7% 99.7%99.7% 99.5% 99.4% 99.5% 99.7% 99.3% 2 98.8% 99.4% 98.9% 91.7% 94.2%100.7% 99.0% 0.0% 4 98.5% 95.5% 95.7% 78.7% 0.0% 95.0% 72.2% 6 97.9%93.8% 93.0% 63.2% 81.0% 0.0% 8 98.8% 96.6% 89.3% 67.0% 0.0% 10 93.1%85.7% 81.5% 57.3% 12 84.9% 74.3% 72.6% 61.9% 14 84.3% 40.4% 72.7% 67.0%16 81.2% 66.9% 70.2% 51.5% 18 78.6% 71.9% 65.5% 53.9%

Implant Swelling

To investigate the implant swelling, each implant was incubated in 20 mLof PBS (pH 7.4, 0.01M) in a glass scintillation vial and placed in ashaking water bath set at 37° C. and 50 rpm. The implant images wererecorded and summarized in FIG. 12. The results show that brimonidinefree base implants swelled and degraded much faster than those ofbrimonidine tartrate.

The drug releases of brimonidine tartrate formulations in rabbit andmonkey eyes are shown in FIGS. 3 and 4, respectively. The drug releasesof brimonidine free base formulations in rabbit and monkey eyes areshown in FIGS. 5 and 6.

The in vivo drug release profiles were determined by retrieving theimplants from the vitreous humor at designated time points. The implantmass was recorded before and after in vivo implantation to determine thequantity of residual polymer matrix. The drug release rates in bothanimal models showed that Example 4 had the highest release rate,followed by Example 1, then Example 3, then Example 2 demonstrated theslowest drug release rate.

The drug concentration of brimonidine tartrate formulations in theretina (optic nerve) of Albino rabbit eyes are shown in FIG. 7. Allformulations maintained the brimonidine concentration above the humanα2A EC90 (88 nM, 25.7 ng/mL) for more than 3 months. For brimonidinefree base formulations, the drug concentrations in retina (optic nervein rabbit and macula in monkey) were determined, and the results areshown in FIGS. 8 and 9 for rabbit and monkey, respectively. The periodfor brimonidine concentration above the human α2A EC90 in the rabbitoptic nerve was <3 months for all formulations. In a contrast, the timeof brimonidine concentration above the human α2A EC90 in the monkeymacula was >4 months for all formulations except Example 4 that lastedabout one month.

The polymer matrix degradation of brimonidine tartrate and free baseformulations in monkey eyes are shown in FIGS. 10 and 11, respectively.For brimonidine tartrate formulations, less than 50% of matrix wasdegraded for Comparative Example 1 and Comparative Example 2formulations in one year, while that for Comparative Example 3 andComparative Example 4 reached more than 90%. For brimonidine free baseformulations, all formulations became small and hard to handle after onemonth, except Example 2, that the polymer matrix was expected to lastfor about six months. The in vitro matrix degradation observationmatches the in vivo results.

The polymer matrix degradation of brimonidine tartrate and free baseformulations in rabbit eyes were analyzed by photo images, and thematrix degradation time is longer than 6 months for brimonidine tartrateformulations and shorter than 4 months for brimonidine free baseformulations.

The polymers used in the formulations include, but not limited to,poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). They aresummarized in Table A.

The four brimonidine free base formulations demonstrated implants withcontrolled drug release from one to four months and polymer matrixeslasting for less than two times the drug release duration. In contrast,the brimonidine tartrate formulations delivered the drug for acomparable duration as the brimonidine free base formulations, but thepolymer matrix lasted more than two times of the drug release duration.

Although this invention has been disclosed in the context of certainpreferred embodiments and examples, it will be understood by thoseskilled in the art that the present invention extends beyond thespecifically disclosed embodiments to other alternative embodimentsand/or uses of the invention and obvious modifications and equivalentsthereof. In addition while the number of variations of the inventionhave been shown and described in detail, other modifications, which arewithin the scope of this invention, will be readily apparent to those ofskill in the art based on this disclosure. It is also contemplated thatvarious combinations or subcombinations of the specific features andaspects of the embodiments can be made and still fall within the scopeof the invention. Accordingly, it should be understood that variousfeatures and aspects of the disclosed embodiments can be combined with,or substituted for, one another in order to perform varying modes of thedisclosed invention. Thus, it is intended that the scope of the presentinvention herein disclosed should not be limited by the particulardisclosed embodiments described above, but should be determined only bya fair reading of the claims.

What is claimed is:
 1. A solid intraocular implant for the treatment of a posterior ocular condition in a human patient, the solid intraocular implant comprising: a brimonidine free base in an amount of about 40% by weight to about 60% by weight of the implant, based on the total weight of the implant; and a biodegradable polymer matrix comprising an acid end-capped poly (D, L-lactide) polymer and a 75:25 poly (D,L-lactide-co-glycolide) polymer; wherein the weight ratio of the acid end-capped poly (D, L-lactide) polymer to the 75:25 poly (D,L-lactide-co-glycolide) polymer is 1:1; and wherein the implant has a polymer matrix degradation time in the range of about three months to about six months when placed in the eye of a human.
 2. The implant of claim 1, wherein the brimonidine free base is present in an amount of about 50% by weight of the implant, based on the total weight of the implant.
 3. The implant of claim 2, wherein the implant has a brimonidine free base delivery duration of two months to four months when placed in the eye of a human.
 4. The implant of claim 1, wherein the acid end-capped poly (D, L-lactide) polymer is present in an about of about 25% by weight.
 5. The implant of claim 1, wherein the 75:25 poly (D,L-lactide-co-glycolide) polymer is present in an about of about 25% by weight.
 6. The implant of claim 5, wherein the total weight of the implant is about 800 μg. 